The activin receptor, type II A (ActRIIA or ACVR2A) is a high affinity receptor for the activin proteins as well as other members of the TGF-beta superfamily. ActRIIA is generally thought to transduce signals that lead to the phosphorylation of one or more SMAD transcription factors, particularly SMADs 1, 2, 3 and 5. ActRIIA has been implicated in the regulation of a wide range of biological processes, including bone formation, muscle formation, red blood cell formation, tumor growth, immune function and the production of reproductive hormones, such as FSH.
Follicle-stimulating hormone (FSH) is produced by the anterior pituitary gland and regulates gonadal function, including the generation and maturation of gametes. FSH secretion from the pituitary is regulated by gonadotropin-releasing hormone (GnRH) from the brain in concert with gonadal hormones and paracrine effectors originating in the pituitary. Activin was originally identified by its ability to increase FSH secretion from pituitary gonadotropes, and activin-mediated signaling, in part through activin receptor type IIA (ActRIIA), is now thought to promote FSH secretion through actions at multiple regulatory levels (Gregory et al., 2004, Semin Reprod Med 22:253-267).
FSH release is necessary for ovulation in females and for maturation of sperm in males. In females, FSH stimulates follicular granulosa cell proliferation in the ovary and impacts synthesis of estrogen, a hormone which is integral to follicular maturation and ovulation. In males, FSH is involved in the maturation of sperm cells. More specifically, FSH action in males is directed at the Sertoli cells, which are a recognized target of the hormone and which support the process of sperm maturation (spermatogenesis). FSH is also produced in the prostate, where it is an important mediator of cell growth.
Accordingly, inhibitors of FSH release are useful as contraceptive agents in both males and females.
In addition to the function in fertility, FSH also plays a role in several disease states. Increased levels of FSH receptor are associated with prostate cancer, with the highest levels associated with hormone-refractory prostate cancer. Prostate cancer is the most common cancer in American men, with more than 200,000 new cases diagnosed each year, and approximately 30,000 deaths due to prostate cancer are projected for 2010 (Jemal A. et al. Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010). Approximately 40% of individuals treated with surgery or radiation will develop recurrent prostate cancer (Walsh P C, Retik A B, Vaughan E D, eds. Campbell's Urology. 7th ed. Philadelphia, Pa.: WB Saunders Company; 1998). The most common treatment for recurrent prostate cancer is the suppression of testicular testosterone production via orchiectomy, estrogen treatment, antiandrogen administration, and/or GnRH agonist/antagonist treatment. This usually results in remission for 2-3 years, after which time prostate cancer becomes “hormone refractory,” meaning that it develops the ability to grow despite the reduction of blood androgen concentrations to castrate levels. Consequently, improved compositions and methods are needed for treating prostate cancer, in particular hormone-refractory prostate cancer.
Pituitary tumors (adenomas) are non-cancerous growths that typically affect different hormone-producing regions, depending on the specific location of the tumor. Pituitary tumors account for about 15% of intracranial tumors, and are associated with significant morbidity due to local compressive effects, hormonal hypersecretion, or treatment-associated endocrine deficiency (Heaney A. P., et al.: Molecular Pathogenesis of Pituitary Tumors. In: Oxford Textbook of Endocrinology, Wass J. A. H. and Shalet S. M., (Eds.), Oxford University Press, Oxford, 2002). The great majority of pituitary adenomas are benign and are relatively slow growing. Pituitary tumors may, however, lead to overproduction of one or more of the pituitary hormones. FSH-secreting pituitary tumors often lead to the development of multicystic ovaries and to elevated estradiol levels. In turn, increases in estradiol levels contribute to health risks including endometrial and prostate cancer. Consequently, improved compositions and methods are needed for treating symptoms associated with FSH-secreting pituitary tumors.
The FSH signaling pathway has been associated with tumor angiogenesis in a wide range of tumor types. Radu A, et al. N Engl J Med. 2010 Oct. 21; 363(17):1621-30. Accordingly, compounds that inhibit FSH secretion are useful in a variety of treatments.
The disclosure provides, in part, antagonists of ActRIIA that may be used to inhibit FSH production as well as other uses.